Neurons communicate across synapses by secreting neurotransmitters. Understanding the molecular mechanisms that regulate neurotransmitter release is central in better understanding brain function, such as learning and memory. In addition, it may also allow us to develop therapeutic strategies to treat certain neurological diseases in which neurotransmitter release needs to be regulated. Recent studies have identified many key molecules which regulate neurotransmitter release in presynaptic neurons. One of these proteins, VAP-33, is a presynaptic plasma membrane protein found to interact with the synaptic vesicle protein VAMP and a voltage-gated Ca channel and thereby may regulate synaptic vesicle docking and fusion. In this proposal, I would like to study the potential role of VAP-33 in regulating neurotransmitter release. Specifically, I would like to determine the regional and subcellular localization of VAP-33 in mammalian brain, the possible physiological effects of VAP-33-Ca 2+ channel interaction on channel function and characterize the interaction of VAP-33 with different types of Ca 2+ channels, VAMP and other proteins involved in the assembly of synaptic vesicle fusion complexes. Furthermore, I would like to examine VAP-33 function in the synaptic transmission of sympathetic neurons by blocking potential VAP-33-Ca 2+ channel interactions.